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IntroductionBlood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.MethodsOlder adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE ?4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4.ResultsBBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers.DiscussionAPOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade.HighlightsGray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

Systemic amyloidosis involves the deposition of misfolded proteins in organs/tissues, leading to progressive organ dysfunction and failure. Congo red is the gold-standard chemical stain for visualizing amyloid deposits in tissue, showing birefringence under polarization microscopy. However, Congo red staining is tedious and costly to perform, and prone to false diagnoses due to variations in amyloid amount, staining quality and manual examination of tissue under a polarization microscope. We report virtual birefringence imaging and virtual Congo red staining of label-free human tissue to show that a single neural network can transform autofluorescence images of label-free tissue into brightfield and polarized microscopy images, matching their histochemically stained versions. Blind testing with quantitative metrics and pathologist evaluations on cardiac tissue showed that our virtually stained polarization and brightfield images highlight amyloid patterns in a consistent manner, mitigating challenges due to variations in chemical staining quality and manual imaging processes in the clinical workflow.

IntroductionUnderstanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment.MethodsUsing data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline.ResultsCompared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline.DiscussionDifferences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial.HighlightsRepresentative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.

Background and objectivesAmyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old.MethodsThis was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors.ResultsThe sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline.DiscussionAmyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

BACKGROUND: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. OBJECTIVES: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). METHODS: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). RESULTS: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimers disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P

We present structural models for three different amyloid fibril polymorphs prepared from amylin20–29 (sequence SNNFGAILSS) and amyloid-β25–35 (Aβ25–35) (sequence GSNKGAIIGLM) peptides. These models are based on the amide C=O bond and Ramachandran ψ-dihedral angle data from Raman spectroscopy, which were used as structural constraints to guide molecular dynamics (MD) simulations. The resulting structural models indicate that the basic structural motif of amylin20–29 and Aβ25–35 fibrils is extended β-strands. Our data indicate that amylin20–29 forms both antiparallel and parallel β-sheet fibril polymorphs, while Aβ25–35 forms a parallel β-sheet fibril structure. Overall, our work lays the foundation for using Raman spectroscopy in conjunction with MD simulations to determine detailed molecular-level structural models of amyloid fibrils in a manner that complements gold-standard techniques, such as solid-state nuclear magnetic resonance and cryogenic electron microscopy. [ABSTRACT FROM AUTHOR]

COVID-19 infection is associated with a variety of vascular occlusive morbidities. However, a comprehensive understanding of how this virus can induce vascular complications remains lacking. Here, we show that a peptide fragment of SARS-CoV-2 spike protein, S192 (sequence 192-211), is capable of forming amyloid-like aggregates that can induce agglutination of red blood cells, which was not observed with low- and non-aggregated S192 peptide. We subsequently screened eight amyloid-binding molecules and identified BAM1-EG6, a benzothiazole amphiphile, as a promising candidate capable of binding to aggregated S192 and partially inhibiting its agglutination activity. These results provide new insight into a potential molecular mechanism for the capability of spike protein metabolites to contribute to COVID-19-related blood complications and suggest a new therapeutic approach for combating microvascular morbidities in COVID-19 patients.

BACKGROUND: In Alzheimers disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aβ) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Amyloid fibrils of tau are increasingly accepted as a cause of neuronal death and brain atrophy in Alzheimer's disease (AD). Diminishing tau aggregation is a promising strategy in the search for efficacious AD therapeutics. Previously, our laboratory designed a six-residue, nonnatural amino acid inhibitor D-TLKIVW peptide (6-DP), which can prevent tau aggregation in vitro. However, it cannot block cell-to-cell transmission of tau aggregation. Here, we find D-TLKIVWC (7-DP), a d-cysteine extension of 6-DP, not only prevents tau aggregation but also fragments tau fibrils extracted from AD brains to neutralize their seeding ability and protect neuronal cells from tau-induced toxicity. To facilitate the transport of 7-DP across the blood-brain barrier, we conjugated it to magnetic nanoparticles (MNPs). The MNPs-DP complex retains the inhibition and fragmentation properties of 7-DP alone. Ten weeks of MNPs-DP treatment appear to reverse neurological deficits in the PS19 mouse model of AD. This work offers a direction for development of therapies to target tau fibrils.

IntroductionTrialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials.MethodsWe used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants' responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status.ResultsReactions to disclosure did not significantly differ among participant groups based on self-reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self-reporting Hispanic/Latino ethnicity were observed to have higher mean IES in the elevated amyloid group.DiscussionThese results support continued use of current disclosure methods in preclinical AD trials.

IntroductionAlzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.MethodsWe crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.ResultsGenetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was maintained across ages and sexes, with observable strain-specific variations in AD-related phenotypes. Comparative gene expression analysis indicated correlations between mouse strains and human AD.DiscussionIncreasing genetic diversity promotes resilience to AD-related pathogenesis, relative to an inbred C57BL/6J background, reinforcing the importance of genetic diversity in uncovering resilience in the development of AD.HighlightsGenetic diversity's impact on AD in mice was explored. Diverse F1 mouse strains were used for AD study, via the Collaborative Cross. Strain-specific variations in AD pathology, glia, and transcription were found. Strains resilient to plaque formation and plasma neurofilament light chain (NfL) increases were identified. Correlations with human AD transcriptomics were observed.

IntroductionThe BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.MethodsTo elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1K358R knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.ResultsThe presence of the BIN1K358R variant leads to increased cerebral amyloid deposition, with a dampened response of astrocytes and oligodendrocytes, but not microglia, at both the cellular and transcriptional levels. This correlates with decreased neurofilament light chain in both plasma and brain tissue. Synaptic densities are significantly increased in both wild-type and 5xFAD backgrounds homozygous for the BIN1K358R variant.DiscussionThe BIN1 K358R variant modulates amyloid pathology in 5xFAD mice, attenuates the astrocytic and oligodendrocytic responses to amyloid plaques, decreases damage markers, and elevates synaptic densities.HighlightsBIN1 rs138047593 (K358R) coding variant is associated with increased risk of LOAD. BIN1 K358R variant increases amyloid plaque load in 12-month-old 5xFAD mice. BIN1 K358R variant dampens astrocytic and oligodendrocytic response to plaques. BIN1 K358R variant decreases neuronal damage in 5xFAD mice. BIN1 K358R upregulates synaptic densities and modulates synaptic transmission.

The absence of a natural animal model is one of the main challenges in Alzheimers disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimers disease.

It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

Diffusion MRI (dMRI) can be used to probe microstructural properties of brain tissue and holds great promise as a means to non-invasively map Alzheimer's disease (AD) pathology. Few studies have evaluated multi-shell dMRI models such as neurite orientation dispersion and density imaging (NODDI) and mean apparent propagator (MAP)-MRI in cortical gray matter where many of the earliest histopathological changes occur in AD. Here, we investigated the relationship between CSF pTau181 and Aβ1-42 burden and regional cortical NODDI and MAP-MRI indices in 46 cognitively unimpaired individuals, 18 with mild cognitive impairment, and two with dementia (mean age: 71.8 ± 6.2 years) from the Alzheimer's Disease Neuroimaging Initiative. We compared findings to more conventional cortical thickness measures. Lower CSF Aβ1-42 and higher pTau181 were associated with cortical dMRI measures reflecting less hindered or restricted diffusion and greater diffusivity. Cortical dMRI measures, but not cortical thickness measures, were more widely associated with Aβ1-42 than pTau181 and better distinguished Aβ+ from Aβ- participants than pTau+ from pTau- participants. dMRI associations mediated the relationship between CSF markers and delayed logical memory performance, commonly impaired in early AD. dMRI metrics sensitive to early AD pathogenesis and microstructural damage may be better measures of subtle neurodegeneration in comparison to standard cortical thickness and help to elucidate mechanisms underlying cognitive decline.

INTRODUCTION: Anti-amyloid therapies are at the forefront of efforts to treat Alzheimers disease (AD). Identifying amyloid risk factors may aid screening and intervention strategies. While veterans face increased exposure to risk factors, whether they face a greater neuropathologic amyloid burden is not well understood. METHODS: Male decedents donating to two Alzheimers Disease Research Center (ADRC) brain banks from 1986 to 2018 with categorized neuritic plaque density and neurofibrillary tangles (n = 597) were included. Using generalized ordered logistic regression we modeled each outcomes association with military history adjusting for age and death year. RESULTS: Having served in the military (60% of sample) is associated with post mortem neuritic amyloid plaque (for each comparison of higher to lower C scores OR = 1.26; 95% confidence interval [CI] = 1.06-1.49) and tau pathology (B score OR = 1.10; 95% CI = 1.08-1.12). DISCUSSION: This is the first study, to our knowledge, finding increased levels of verified AD neuropathology in those with military service. Targeted veteran AD therapies is a pressing need.

PURPOSE: To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [18F]flutemetamol and [18F]florbetaben. METHODS: Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [18F]flutemetamol (N = 175) or [18F]florbetaben (N = 75). PET scans were acquired in list-mode (90-110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. RESULTS: At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [18F]flutemetamol and [18F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were  80% for both tracers. CONCLUSION: This proof-of-concept study showed that for both [18F]flutemetamol and [18F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

Alzheimers disease and Type 2 diabetes are two epidemiologically linked diseases which are closely associated with the misfolding and aggregation of amyloid proteins amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP), respectively. The co-aggregation of the two amyloid proteins is regarded as the fundamental molecular mechanism underlying their pathological association. The green tea extract epigallocatechin-3-gallate (EGCG) has been extensively demonstrated to inhibit the amyloid aggregation of Aβ and hIAPP proteins. However, its potential role in amyloid co-aggregation has not been thoroughly investigated. In this study, we employed the enhanced-sampling replica exchange molecular dynamics simulation (REMD) method to investigate the effect of EGCG on the co-aggregation of Aβ and hIAPP. We found that EGCG molecules substantially diminish the β-sheet structures within the amyloid core regions of Aβ and hIAPP in their co-aggregates. Through hydrogen-bond, π-π and cation-π interactions targeting polar and aromatic residues of Aβ and hIAPP, EGCG effectively attenuates both inter-chain and intra-chain interactions within the co-aggregates. All these findings indicated that EGCG can effectively inhibit the co-aggregation of Aβ and hIAPP. Our study expands the potential applications of EGCG as an anti-amyloidosis agent and provides therapeutic options for the pathological association of amyloid misfolding disorders.

Cerebellar amyloid-β (Aβ) plaques are a component of the diagnostic criteria used in Thal staging and ABC scoring for Alzheimer disease (AD) neuropathologic change. However, Aβ deposits in this anatomic compartment are unique and under-characterized; and their relationship with other pathological findings are largely undefined. In 73 cases of pure or mixed AD with an A3 score in the ABC criteria, parenchymal (plaques) and vascular (cerebral amyloid angiopathy [CAA]) cerebellar Aβ-42 deposits were characterized with respect to localization, morphology, density, and intensity. Over 85% of cases demonstrated cerebellar Aβ-42 parenchymal staining that correlated with a Braak stage V-VI/B3 score (p

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Aβ aggregation leads to the formation of both insoluble amyloid fibrils and soluble oligomers. Understanding the structures of Aβ oligomers is important for delineating the mechanism of Aβ aggregation and developing effective therapeutics. Here, we use site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study Aβ42 oligomers prepared by using the protocol of Aβ-derived diffusible ligands. We obtained the EPR spectra of 37 Aβ42 oligomer samples, each spin-labeled at a unique residue position of the Aβ42 sequence. Analysis of the disordered EPR components shows that the N-terminal region has a lower local structural stability. Spin label mobility analysis reveals three structured segments at residues 9-11, 15-22, and 30-40. Intermolecular spin-spin interactions indicate a parallel in-register β-sheet structure, with residues 34-38 forming the structural core. Residues 16-21 also adopt the parallel in-register β-structure, albeit with weaker intermolecular packing. Our results suggest that there is a structural class of Aβ oligomers that adopt fibril-like conformations.

Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts' evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

BACKGROUND: Converging evidence suggests that markers of Alzheimers disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimers disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ- and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimers Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.

Successful cognitive aging is often thought to result from resistance to the accumulation of pathology, resilience to the effects of pathological accumulation, or some combination of the two. While evidence for resilience has been found in typical aging populations, the oldest-old provide us with a unique window into the role of pathological accumulation in impacting cognition. Here, we aimed to assess group differences in measures of amyloid and tau across older age groups using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI age: 60-89) and The 90+ Study (age: 90-101). Additionally, using the ADNI dataset, we performed exploratory analyses of regional cingulate AV-45 SUVRs to assess if amyloid load in particular areas was associated with Top Cognitive Performance (TCP). Consistent with the literature, results showed no group differences in amyloid SUVRs both regionally and in the whole cortex. For tau with AV-1451, we also observed no differences in Braak composite SUVRs. Interestingly, these relationships persisted in the oldest-old. This indicates that Top Cognitive Performance throughout aging does not reflect resistance to amyloid and tau burden, but that other mechanisms may be associated with protection against amyloid and tau related neurodegeneration.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

BACKGROUND: Loneliness has been declared an epidemic associated with negative physical, mental, and cognitive health outcomes such as increased dementia risk. Less is known about the relationship between loneliness and advanced neuroimaging correlates of Alzheimers disease (AD). OBJECTIVE: To assess whether loneliness was associated with advanced neuroimaging markers of AD using neuroimaging data from Framingham Heart Study (FHS) participants without dementia. METHODS: In this cross-sectional observational analysis, we used functional connectivity MRI (fcMRI), amyloid-β (Aβ) PET, and tau PET imaging data collected between 2016 and 2019 on eligible FHS cohort participants. Loneliness was defined as feeling lonely at least one day in the past week. The primary fcMRI marker was Default Mode Network intra-network connectivity. The primary PET imaging markers were Aβ deposition in precuneal and FLR (frontal, lateral parietal and lateral temporal, retrosplenial) regions, and tau deposition in the amygdala, entorhinal, and rhinal regions. RESULTS: Of 381 participants (mean age 58 [SD 10]) who met inclusion criteria for fcMRI analysis, 5% were classified as lonely (17/381). No association was observed between loneliness status and network changes. Of 424 participants (mean age 58 [SD = 10]) meeting inclusion criteria for PET analyses, 5% (21/424) were lonely; no associations were observed between loneliness and either Aβ or tau deposition in primary regions of interest. CONCLUSIONS: In this cross-sectional study, there were no observable associations between loneliness and select fcMRI, Aβ PET, and tau PET neuroimaging markers of AD risk. These findings merit further investigation in prospective studies of community-based cohorts.

BackgroundPrior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples.MethodsThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included.ResultsData collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators.ConclusionThe pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

IntroductionThere is no consensus on either the definition of successful cognitive aging (SA) or the underlying neural mechanisms.MethodsWe examined the agreement between new and existing definitions using: (1) a novel measure, the cognitive age gap (SA-CAG, cognitive-predicted age minus chronological age), (2) composite scores for episodic memory (SA-EM), (3) non-memory cognition (SA-NM), and (4) the California Verbal Learning Test (SA-CVLT).ResultsFair to moderate strength of agreement was found between the four definitions. Most SA groups showed greater cortical thickness compared to typical aging (TA), especially in the anterior cingulate and midcingulate cortices and medial temporal lobes. Greater hippocampal volume was found in all SA groups except SA-NM. Lower entorhinal 18 F-Flortaucipir (FTP) uptake was found in all SA groups.DiscussionThese findings suggest that a feature of SA, regardless of its exact definition, is resistance to tau pathology and preserved cortical integrity, especially in the anterior cingulate and midcingulate cortices.HighlightsDifferent approaches have been used to define successful cognitive aging (SA). Regardless of definition, different SA groups have similar brain features. SA individuals have greater anterior cingulate thickness and hippocampal volume. Lower entorhinal tau deposition, but not amyloid beta is related to SA. A combination of cortical integrity and resistance to tau may be features of SA.

AbstractBackgroundMethodsResultsConclusionsThe NEURO-TTRansform trial showed that after 66 weeks of treatment, eplontersen significantly reduced neuropathic impairment and improved quality of life (QoL) in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN). In this secondary analysis from NEURO-TTRansform, autonomic impairment, and the impact of eplontersen on autonomic impairment progression was evaluated through 85 weeks in patients randomised to eplontersen (n = 144) versus external placebo (n = 60; through Week 66 from the NEURO-TTR trial).Change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, and the Neuropathy Symptoms and Change (NSC) total score was evaluated. Exploratory assessments were change in autonomic components of these instruments, Composite Autonomic Symptom Score-31 (COMPASS-31) total score, and nutritional status (modified body mass index [mBMI]).Patients reported profound autonomic dysfunction at baseline. Improvements with eplontersen versus placebo were observed up to Week 66 in autonomic components of mNIS+7, Norfolk QoL-DN, NSC, and mBMI; eplontersen results were sustained up to Week 85, including improvements in COMPASS-31 (Week 81).Eplontersen demonstrated benefit across multiple measures of autonomic impairment known to progress rapidly and negatively impact QoL without treatment, without deterioration in nutritional status. [ABSTRACT FROM AUTHOR]

Mutations in ITM2B cause familial British, Danish, Chinese, and Korean dementias. In familial British dementia (FBD), a mutation in the stop codon of the ITM2B gene (also known as BRI2) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer's disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. The ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. The pathological examination of post-mortem tissue supports the presence of ABri in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. These data have implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood. Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis. Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted. Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions. Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions. [ABSTRACT FROM AUTHOR]

This preclinical AD CSF proteome study identified a panel of 12-CSF markers detecting amyloid positivity and clinical progression to AD with high accuracy; some of these CSF proteins related to immune function, neurotrophic processes, energy metabolism and endolysosomal functioning (e.g., ITGB2, CLEC5A, IGFBP-1, CST3) changed before amyloid positivity is established. [ABSTRACT FROM AUTHOR]

Biondi bodies are filamentous amyloid inclusions of unknown composition in ependymal cells of the choroid plexuses, ependymal cells lining cerebral ventricles and ependymal cells of the central canal of the spinal cord. Their formation is age-dependent and they are commonly associated with a variety of neurodegenerative conditions, including Alzheimer's disease and Lewy body disorders. Here, we show that Biondi bodies are strongly immunoreactive with TMEM239, an antibody specific for inclusions of transmembrane protein 106B (TMEM106B). Biondi bodies were labelled by both this antibody and the amyloid dye pFTAA. Many Biondi bodies were also labelled for TMEM106B and the lysosomal markers Hexosaminidase A and Cathepsin D. By transmission immuno-electron microscopy, Biondi bodies of choroid plexuses were decorated by TMEM239 and were associated with structures that resembled residual bodies or secondary lysosomes. By electron cryo-microscopy, TMEM106B filaments from Biondi bodies of choroid plexuses were similar (Biondi variant), but not identical, to the fold I that was previously identified in filaments from brain parenchyma. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α‐synuclein cross‐β amyloid filaments in the brain. Previous structural studies of these filaments by cryo‐electron microscopy (cryo‐EM) revealed three discrete folds distinct from α‐synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo‐EM to identify a novel, low‐populated MSA filament subtype (designated Type I2) in addition to a predominant class comprising MSA Type II2 filaments. The 3.3‐Å resolution structure of the Type I2 filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA‐specific folds of α‐synuclein filaments and have implications for designing MSA diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

Systemic ALys amyloidosis is a debilitating protein misfolding disease that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 Å cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. As the conformation of lysozyme in the fibril is otherwise fundamentally different from native lysozyme, our data provide a structural rationale for the need of protein unfolding in the development of systemic ALys amyloidosis. Here the authors perform the reconstruction and analysis of pathological ALys amyloid fibrils extracted from fat tissue from a patient carrying the D87G variant. They reveal an intact amyloid fibril with no evidence of proteolysis and four intact disulphide bonds. [ABSTRACT FROM AUTHOR]

Alzheimer's disease, the most common form of dementia among older adults, slowly destroys memory and thinking skills. In recent years, scientists have made tremendous progress in understanding Alzheimer's disease, still, they do not yet fully understand what causes the disease. This article proposes a novel etiology for Alzheimer's disease. Our hypothesis developed from a review of nuclear medicine scans, in which the authors observed a significant increase in nasal turbinate vasodilation and blood pooling in patients with hypertension, sleep apnea, diabetes and/or obesity, all risk factors for Alzheimer's disease. The authors propose that nasal turbinate vasodilation and resultant blood pooling lead to the obstruction of normal nasal lymphatic clearance of cerebrospinal fluid and its waste products from the brain. The nasal turbinate vasodilation, due to increased parasympathetic activity, occurs alongside the well-established increased sympathetic activity of the cardiovascular system as seen in patients with hypertension. The increased parasympathetic activity is likely due to an autonomic imbalance secondary to the increase in worldwide consumption of highly processed food associated with dysregulation of the glucose regulatory system. The authors' hypothesis offers a novel mechanism and a new paradigm for the etiology of Alzheimer's disease and helps explain the rapid worldwide rise in the disease and other dementias which are expected to double in the next 20 years. This new paradigm provides compelling evidence for the modulation of the parasympathetic nervous system as a novel treatment strategy for Alzheimer's disease and other degenerative brain diseases, specifically targeting nasal turbinate lymphatic flow. [ABSTRACT FROM AUTHOR]

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution. [ABSTRACT FROM AUTHOR]

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional MRI activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive ageing. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analysed subsequent memory functional MRI data from individuals with SCD, MCI and AD dementia as well as healthy controls and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-centre DELCODE study (n = 468). Based on the individual participants' whole-brain functional MRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity and APOE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to healthy controls, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ɛ4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients. [ABSTRACT FROM AUTHOR]

Serum amyloid A (SAA) is a small protein consisting of 104 residues and, under physiological conditions, exists mainly in hexameric form. It belongs to the positive acute-phase proteins, which means that its plasma concentration increases rapidly in response to injury, inflammation, and infection. The accumulation of SAA molecules promotes the formation of amyloid aggregates, which deposit extracellularly in many organs, causing their dysfunction. In our previous work, we successfully designed a peptidomimetic that inhibited the aggregation of amyloidogenic SAA fragments. In the present paper, we show how the same inhibitor, named saa3Dip, affects the oligomerization and aggregation processes of MetSAA1.1 protein. The thioflavin T assay showed that saa3Dip inhibited its fibrillization. The measurement of the internal fluorophore fluorescence (Trp) showed differences that occurred in the tertiary structure of MetSAA1.1 in the presence of the inhibitor, which was also confirmed by CD spectra in the aromatic range. FTIR results suggested that saa3Dip could stabilize some fragments of the native structure of MetSAA1.1, which was confirmed by determining the melting temperature (Tm) of the protein–inhibitor complex. AFM images demonstrated that the presence of saa3Dip prevented the formation of large SAA aggregates. Our results suggest that saa3Dip stabilizes the native conformation of MetSAA1.1. [ABSTRACT FROM AUTHOR]

Chronic stress and glucocorticoids (GCs, the stress hormones of the body) are implicated in the tau, amyloid β (Aβ), and neuroinflammatory pathology that is characteristic of Alzheimer's disease. Stress and GCs activate kinases and inhibit proteostasis mechanisms, thus driving tau hyperphosphorylation, aggregation, and secretion/spreading through the brain. Stress and GCs promote Aβ pathology by increasing the expression and amyloidogenic processing of amyloid precursor protein (APP) and by impairing APP and Aβ clearance mechanisms. Stress and GCs stimulate neuroinflammation through upregulation of the inflammasome and damage-associated molecular pattern (DAMP) receptors, thereby promoting the secretion of proinflammatory cytokines. Stress and GCs induce aberrant glial cell functioning, leading to over-pruning of synapses, glutamate excitotoxicity, and decreased integrity of the blood–brain barrier (BBB) and glymphatic clearance systems. Chronic stress and the accompanying long-term elevation of glucocorticoids (GCs), the stress hormones of the body, increase the risk and accelerate the progression of Alzheimer's disease (AD). Signatures of AD include intracellular tau (MAPT) tangles, extracellular amyloid β (Aβ) plaques, and neuroinflammation. A growing body of work indicates that stress and GCs initiate cellular processes underlying these pathologies through dysregulation of protein homeostasis and trafficking, mitochondrial bioenergetics, and response to damage-associated stimuli. In this review, we integrate findings from mechanistic studies in rodent and cellular models, wherein defined chronic stress protocols or GC administration have been shown to elicit AD-related pathology. We specifically discuss the effects of chronic stress and GCs on tau pathogenesis, including hyperphosphorylation, aggregation, and spreading, amyloid precursor protein (APP) processing and trafficking culminating in Aβ production, immune priming by proinflammatory cytokines and disease-associated molecular patterns, and alterations to glial cell and blood–brain barrier (BBB) function. [ABSTRACT FROM AUTHOR]

Over 200 genetic mutations in copper-zinc superoxide dismutase (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). Among these, two ALS-causing mutants, histidine-46→ arginine (H46R) and glycine-85→ arginine (G85R), exhibit a decreased capacity to bind metal ions. Here, we report two cryo-electron microscopy structures of amyloid fibrils formed by H46R and G85R. These mutations lead to the formation of amyloid fibrils with unique structures distinct from those of the native fibril. The core of these fibrils features a serpentine arrangement with seven or eight β strands, secured by a hydrophobic cavity and a salt bridge between arginine-85 and aspartic acid-101 in the G85R fibril. We demonstrate that these mutant fibrils are notably more toxic and capable of promoting the aggregation of wild-type SOD1 more effectively, causing mitochondrial impairment and activating ferroptosis in cell cultures, compared to wild-type SOD1 fibrils. Our study provides insights into the structural mechanisms by which SOD1 mutants aggregate and induce cytotoxicity in ALS. [ABSTRACT FROM AUTHOR]

Objective: We intended to investigate the relationships between visual sensory impairment (VSI) or auditory sensory impairment (ASI) and brain pathological changes associated with cognitive decline in older adults. Methods: We primarily tried to examine whether each sensory impairment is related to Alzheimer's disease (AD) pathology, specifically beta-amyloid (Aβ) deposition, through both cross-sectional and longitudinal approaches in cognitively unimpaired older adults. Self-report questionnaires on vision and hearing status were administered at the baseline. Neuroimaging scans including brain [11C] Pittsburgh Compound B PET and MRI, as well as clinical assessments, were performed at baseline and 2-year follow-up. Results: Cross-sectional analyses showed that the VSI-positive group had significantly higher Aβ deposition than the VSI-negative group, whereas there was no significant association between ASI positivity and Aβ deposition. Longitudinal analyses revealed that VSI positivity at baseline was significantly associated with increased Aβ deposition over 2 years (β = 0.153, p = 0.025), although ASI positivity was not (β = 0.045, p = 0.518). VSI positivity at baseline was also significantly associated with greater atrophic changes in AD-related brain regions over the 2-year follow-up period (β = -0.207, p = 0.005), whereas ASI positivity was not (β = 0.024, p = 0.753). Neither VSI nor ASI positivity was related to cerebrovascular injury, as measured based on the white matter hyperintensity volume. Conclusion: The findings suggest that VSI is probably related to AD-specific pathological changes, which possibly mediate the reported relationship between VSI and cognitive decline. In contrast, ASI appears not associated with AD pathologies but may contribute to cognitive decline via other mechanisms. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset. [ABSTRACT FROM AUTHOR]

This article examines the relationship between cholesterol levels and Alzheimer's disease (AD), beginning with the early observation that individuals who died from heart attacks often had brain amyloid deposition. Subsequent animal model research proved that high cholesterol could hasten amyloid accumulation. In contrast, cholesterol-lowering treatments appeared to counteract this effect. Human autopsy studies reinforced the cholesterol-AD connection, revealing that higher cholesterol levels during midlife significantly correlated with higher brain amyloid pathology. This effect was especially pronounced in individuals aged 40 to 55. Epidemiological data supported animal research and human tissue observations and suggested that managing cholesterol levels in midlife could reduce the risk of developing AD. We analyze the main observational studies and clinical trials on the efficacy of statins. While observational data often suggest a potential protective effect against AD, clinical trials have not consistently shown benefit. The failure of these trials to demonstrate a clear advantage is partially attributed to multiple factors, including the timing of statin therapy, the type of statin and the appropriate selection of patients for treatment. Many studies failed to target individuals who might benefit most from early intervention, such as high-risk patients like APOE4 carriers. The review addresses how cholesterol is implicated in AD through various biological pathways, the potential preventive role of cholesterol management as suggested by observational studies, and the difficulties encountered in clinical trials, particularly related to statin use. The paper highlights the need to explore alternate therapeutic targets and mechanisms that escape statin intervention. [ABSTRACT FROM AUTHOR]

The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer's disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients' recruitment in therapeutic clinical trials. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases. Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR. Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic. [ABSTRACT FROM AUTHOR]